Sandra J. Horning

PURPOSE: Standardized response criteria are needed to interpret and compare clinical trials and for approval of new therapeutic agents by regulatory agencies. METHODS: The International Working Group response criteria (Cheson et al, J Clin Oncol 17:1244, 1999) were widely adopted, but required reassessment because of identified limitations and the increased use of [18F]fluorodeoxyglucose-positron emission tomography (PET), immunohistochemistry (IHC), and flow cytometry. The International Harmonization Project was convened to provide updated recommendations. RESULTS: New guidelines are presented incorporating PET, IHC, and flow cytometry for definitions of response in non-Hodgkin's and Hodgkin's lymphoma. Standardized definitions of end points are provided. CONCLUSION: We hope that these guidelines will be adopted widely by study groups, pharmaceutical and biotechnology companies, and regulatory agencies to facilitate the development of new and more effective therapies to improve the outcome of patients with lymphoma.

Standardized guidelines for response assessment are needed to ensure comparability among clinical trials in non-Hodgkin's lymphomas (NHL). To achieve this, two meetings were convened among United States and international lymphoma experts representing medical hematology/oncology, radiology, radiation oncology, and pathology to review currently used response definitions and to develop a uniform set of criteria for assessing response in clinical trials. The criteria that were developed include anatomic definitions of response, with normal lymph node size after treatment of 1.5 cm in the longest transverse diameter by computer-assisted tomography scan. A designation of complete response/unconfirmed was adopted to include patients with a greater than 75% reduction in tumor size after therapy but with a residual mass, to include patients-especially those with large-cell NHL-who may not have residual disease. Single-photon emission computed tomography gallium scans are encouraged as a valuable adjunct to assessment of patients with large-cell NHL, but such scans require appropriate expertise. Flow cytometric, cytogenetic, and molecular studies are not currently included in response definitions. Response rates may be the most important objective in phase II trials where the activity of a new agent is important and may provide support for approval by regulatory agencies. However, the goals of most phase III trials are to identify therapies that will prolong the progression-free survival, if not the overall survival, of the treated patients. We hope that these guidelines will serve to improve communication among investigators and comparability among clinical trials until clinically relevant laboratory and imaging studies are identified and become more widely available.

BACKGROUND: Two thirds of patients with advanced Hodgkin's disease are cured with current approaches to treatment. Prediction of the outcome is important to avoid overtreating some patients and to identify others in whom standard treatment is likely to fail. METHODS: Data were collected from 25 centers and study groups on a total of 5141 patients treated with combination chemotherapy for advanced Hodgkin's disease, with or without radiotherapy. The data included the outcome and 19 demographic and clinical characteristics at diagnosis. The end point was freedom from progression of disease. Complete data were available for 1618 patients; the final Cox model was fitted to these data. Data from an additional 2643 patients were used for partial validation. RESULTS: The prognostic score was defined as the number of adverse prognostic factors present at diagnosis. Seven factors had similar independent prognostic effects: a serum albumin level of less than 4 g per deciliter, a hemoglobin level of less than 10.5 g per deciliter, male sex, an age of 45 years or older, stage IV disease (according to the Ann Arbor classification), leukocytosis (a white-cell count of at least 15,000 per cubic millimeter), and lymphocytopenia (a lymphocyte count of less than 600 per cubic millimeter, a count that was less than 8 percent of the white-cell count, or both). The score predicted the rate of freedom from progression of disease as follows: 0, or no factors (7 percent of the patients), 84 percent; 1 (22 percent of the patients), 77 percent; 2 (29 percent of the patients), 67 percent; 3 (23 percent of the patients), 60 percent; 4 (12 percent of the patients), 51 percent; and 5 or higher (7 percent of the patients), 42 percent. CONCLUSIONS: The prognostic score we developed may be useful in designing clinical trials for the treatment of advanced Hodgkin's disease and in making individual therapeutic decisions, but a distinct group of patients at very high risk could not be identified on the basis of routinely documented demographic and clinical characteristics.

PURPOSE: To address early and late treatment failures in older patients with diffuse large B-cell lymphoma (DLBCL), we designed a two-stage randomized trial of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) versus rituximab plus CHOP (R-CHOP), with a second random assignment to maintenance rituximab (MR) or observation in responding patients. PATIENTS AND METHODS: Untreated DLBCL patients who were 60 years or older were randomly assigned to R-CHOP (n = 318) or CHOP (n = 314); 415 responders were randomly assigned to MR (n = 207) or observation (n = 208). The primary end point was failure-free survival (FFS). All P values were two sided. RESULTS: Three-year FFS rate was 53% for R-CHOP patients and 46% for CHOP patients (P = .04) at a median follow-up time of 3.5 years. Two-year FFS rate from second random assignment was 76% for MR compared with 61% for observation (P = .009). No significant differences in survival were seen according to induction or maintenance therapy. FFS was prolonged with MR after CHOP (P = .0004) but not after R-CHOP (P = .81) with 2-year FFS rates from second random assignment of 77%, 79%, 74%, and 45% for R-CHOP, R-CHOP + MR, CHOP + MR, and CHOP, respectively. In a secondary analysis excluding MR patients, R-CHOP alone reduced the risks of treatment failure (P = .003) and death (P = .05) compared with CHOP alone. CONCLUSION: Rituximab administered as induction or maintenance with CHOP chemotherapy significantly prolonged FFS in older DLBCL patients. After R-CHOP, no benefit was provided by MR. These results, which are consistent with an additive effect of rituximab, suggest that future studies could focus on maintenance strategies with novel agents as well as new induction therapies.